The present invention relates to novel semisynthetic macrolides having antibacterial activity and which are useful in the treatment and prevention of bacterial infections. More particularly, the invention relates to 11,12-cyclized erythromycin derivatives, compositions containing such compounds and methods for using the same, as well as processes for making such compounds.
Erythromycins A through D, represented by formula (E) as illustrated below, 
are well-known and potent antibacterial agents, used widely to treat and prevent bacterial infection. As with other antibacterials, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify new erythromycin derivative compounds which possess improved antibacterial activity, which have less potential for developing resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms. Consequently, numerous investigators have prepared chemical derivatives of erythromycin in an attempt to obtain analogs having modified or improved profiles of antibiotic activity.
Kashimura et al. have disclosed 6-O-methylerythromycin derivatives having a tricyclic basic nuclear structure in European Application 559896, published Nov. 11, 1991. Also, Asaka et al. have disclosed 5-O-desoaminylerythronolide derivatives containing a tricyclic carbamate structure in PCT Application WO 93/21200, published Apr. 22, 1992.
Recently erythromycin derivatives containing a variety of substituents at the 6-O position have been disclosed in U.S. Pat. Nos. 5,866,549, 6,075,011 and 6,420,555 B1 as well as PCT Applications WO 00/78773 and WO 03/024986. Furthermore, Ma et. al. have described erythromycin derivatives with aryl groups tethered to the C-6 position in J. Med Chem., 44, pp 4137-4156 (2001).
More recently, erythromycin derivatives containing a lactone moiety at the C11-C12 position have been disclosed in PCT Application WO 02/16380, published Feb. 28, 2002 as well as WO 02/50091 and WO 02/50092, both published Jun. 27, 2002 and WO 03/024986, which published on Mar. 27, 2003.
The present invention provides a novel class of C11-C12 cyclized erythromycin compounds that possess antibacterial activity.
In one aspect of the present invention there are disclosed novel bicyclic erythromycin compounds represented by formula I as illustrated below: 
as well as the pharmaceutically acceptable salts, esters and prodrugs thereof.
In formula I:
A is selected from:
(a) xe2x80x94OH;
(b) xe2x80x94ORp, where Rp is a hydroxy protecting group;
(c) xe2x80x94R1, where R1 is selected from:
1. aryl;
2. substituted aryl;
3. heteroaryl; and
4. substituted heteroaryl;
(d) xe2x80x94OR1, where R1 is as previously defined;
(e) xe2x80x94R2, where R2 is selected from:
1. hydrogen;
2. halogen;
3. C1-C6alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S and N, optionally substituted with one or more substituents selected from halogen, cyano, oxo, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
4. C2-C6 alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S and N, optionally substituted with one or more substituents selected from halogen, cyano, oxo, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
5. C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S and N, optionally substituted with one or more substituents selected from halogen, cyano, oxo, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
(f) xe2x80x94OR2, where R2 is previously defined;
(g) xe2x80x94S(O)nR11, where n=0, 1 or 2, and R11 is selected from hydrogen, R1 and R2, where R1 and R2 are as previously defined
(h) xe2x80x94OC(O)R11, where R11 is as previously defined;
(i) xe2x80x94C(O)R11, where R11 is as previously defined;
(j) xe2x80x94C(O)NHR11, where R11 is as previously defined;
(k) xe2x80x94OC(O)NHR11, where R11 is as previously defined;
(l) xe2x80x94NHC(O)R11, where R11 is as previously defined;
(m) xe2x80x94NHC(O)NHR11, where R11 is as previously defined;
(n) xe2x80x94NHS(O)nR11, where n and R11 are as previously defined;
(o) xe2x80x94NR14R15, where R14 and R15 are each independently R11, where R11 is as previously defined; and
(p) xe2x80x94NHR3, where R3 is an amino protecting group;
B is selected from:
(a) hydrogen;
(b) deuterium;
(c) xe2x80x94CN;
(d) xe2x80x94NO2;
(e) halogen;
(f) xe2x80x94OH;
(g) xe2x80x94R1, where R1 is as previously defined;
(h) xe2x80x94R2, where R2 is as previously defined; and
(i) xe2x80x94ORp, where Rp is as previously defined;
provided that when B is halogen, xe2x80x94NO2, xe2x80x94OH or ORp, A is R1 or R2; or, alternatively, A and B taken together with the carbon atom to which they are attached are selected from:
(a) Cxe2x95x90O;
(b) C(OR2)2, where R2 is as previously defined;
(c) C(SR2)2, where R2 is as previously defined;
(d) C(OR12)(OR13), where R12 and R13 taken together are xe2x80x94(CH2)mxe2x80x94, and where m is 2 or 3;
(e) C(SR12)(SR13), where R12 and R13 taken together are xe2x80x94(CH2)m and, where m is as previously defined,
(f) Cxe2x95x90CR11R14, where R11 and R14 are as previously defined;
(g) Cxe2x95x90Nxe2x80x94Oxe2x80x94R11, where R11 is as previously defined;
(h) Cxe2x95x90NNHR11, where R11 is as previously defined;
(i) Cxe2x95x90NNHC(O)R11, where R11 is as previously defined;
(j) Cxe2x95x90NNxe2x95x90CR11R14, where R11 and R14 are as previously defined;
(k) Cxe2x95x90NNHC(O)NHR11, where R11 is as previously defined;
(l) Cxe2x95x90NNHS(O)nR11, where n and R11 are as previously defined;
(m) Cxe2x95x90NNHR3, where R3 is as previously defined; and
(n) Cxe2x95x90NR11, where R11 is as previously defined;
one of X and Y is hydrogen and the other is selected from:
(a) hydrogen;
(b) deuterium;
(c) xe2x80x94OH;
(d) xe2x80x94ORp, where Rp is as previously defined; and
(e) xe2x80x94NR4R5, where R4 and R5 are each independently selected from:
1. hydrogen; and
2. C1-C12 alkyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or
R4 and R5, taken together with the nitrogen atom to which they are attached form a 3-10 membered heteroalkyl ring containing 0-2 additional hetero atoms selected from O, S and N; or
alternatively, X and Y taken together with the carbon atom to which they are attached are selected from:
(a) Cxe2x95x90O;
(b) Cxe2x95x90NR11, where R11 is as previously defined;
(c) Cxe2x95x90NC(O)R11, where R11 is as previously defined;
(d) Cxe2x95x90Nxe2x80x94OR6, where R6 is selected from:
1. hydrogen;
2. xe2x80x94CH2O(CH2)2OCH3,
3. xe2x80x94CH2O(CH2O)nCH3, where n is as previously defined;
4. xe2x80x94C1-C12 alkyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl and substituted heteroaryl;
5. C3-C12 cycloalkyl;
6. C(O)xe2x80x94C1-C12 alkyl;
7. C(O)xe2x80x94C3-C12 cycloalkyl;
8. C(O)xe2x80x94R1, where R1 is as previously defined; and
9. xe2x80x94Si(Ra)(Rb)(Rc), wherein Ra, Rb and Rc are each independently selected from C1-C12 alkyl, aryl and substituted aryl; and
(e) Cxe2x95x90Nxe2x80x94Oxe2x80x94C(R7)(R8)xe2x80x94Oxe2x80x94R6, where R6 is as previously defined, provided that R6 is not C(O)xe2x80x94C1-C12 alkyl, C(O)xe2x80x94C3-C12 cycloalkyl, or C(O)xe2x80x94R1; and R7 and R8 taken together with the carbon atom to which they are attached form a C3-C12 cycloalkyl group or each is independently selected from:
1. hydrogen; and
2. C1-C12 alkyl;
L is selected from:
(a) xe2x80x94CH(OH)CH3;
(b) C1-C6 alkyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(c) C2-C6 alkenyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
(d) C2-C6 alkynyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
W is selected from:
(a) hydrogen;
(b) xe2x80x94OH;
(c) xe2x80x94CN;
(d) xe2x80x94OR10, where R10 is methyl, optionally substituted with one or more substituents selected from:
1. halogen;
2. deuterium;
3. xe2x80x94CN;
4. xe2x80x94R1, where R1 is as previously defined;
5. xe2x80x94OR11, where R11 is as previously defined;
6. xe2x80x94S(O)nR11, where n and R11 are as previously defined;
7. xe2x80x94OC(O)R11, where R11 is as previously defined;
8. xe2x80x94C(O)R11, where R11 is as previously defined;
9. xe2x80x94C(O)OR11, where R11 is as previously defined;
10. xe2x80x94C(O)NHR11, where R11 is as previously defined;
11. xe2x80x94OC(O)NHR11, where R11 is as previously defined;
12. xe2x80x94NHC(O)R11, where R11 is as previously defined;
13. xe2x80x94NHC(O)NHR11, where R11 is as previously defined; and
14. xe2x80x94NHS(O)nR11, where n and R11 are as previously defined; and
(e) xe2x80x94OC(O)NHR11, where R11 is as previously defined;
Z is selected from:
(a) hydrogen;
(b) halogen; and
(c) C1-C6 alkyl, optionally substituted with one or more substituents selected from halogen, cyano, aryl, substituted aryl, heteroaryl and substituted heteroaryl; and
R2xe2x80x2 is hydrogen or Rp, where Rp, is as previously defined.
In another aspect of the present invention there are disclosed pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier, and treatment of antibacterial infections with such compositions. Suitable carriers and methods of formulation are also disclosed. The compounds and compositions of the present invention have antibacterial activity.
In a further aspect of the present invention there are provided processes for the preparation of 11,12-cyclized erythromycin derivatives of formula (I).